Dr. Sharma: Hello, everyone, and welcome back to another edition of Neonatology Review: Isolette to Crib. I'm Dr. Jyoti Sharma, and I will be your host for this episode. The purpose of this podcast is to review high-yield common topics in neonatology. While our focus is geared towards perinatal and neonatal boards, anyone learning or studying neonatology will find this podcast useful.

For this episode, our guest is Dr. Diane Lee, who is a neonatologist with us here at Children's Mercy Hospital in Kansas City. And her area of interest is the care of the extremely low birth weight infants. She is one of our neonatologists on our small baby unit team. Good afternoon, Dr. Lee. How are you doing today? Welcome.

Dr. Lee: Hi, Dr. Sharma. I'm doing fantastic. And thank you for inviting me. I'm so excited to be back today.

Dr. Sharma: Great. So Dr. Lee is joining us today to talk about perinatal and neonatal CMV infection. If you remember, in the previous episode, she talked about the epidemiology, pathogenesis and clinical manifestations of congenital CMV infection. And in this episode, we will discuss the evaluation, management and prevention of perinatal and neonatal CMV infection. Dr. Lee, can we start with the important aspects of the evaluation of a newborn with suspected congenital CMV infection?

Dr. Lee: Yes, Dr. Sharma. The evaluation of suspected CMV infection is often prompted by an astute clinician with very thorough differential diagnoses because the majority of affected neonates are clinically asymptomatic. Common clinical clues that frequently prompts a CMV workup include a preterm or growth-restricted infant with microcephaly, thrombocytopenia, hepatomegaly or microcephaly or an abnormal CNS imaging, such as a head ultrasound with calcifications.

Dr. Sharma: Dr. Lee, these are such important points. In the clinical setting, we have to think about congenital CMV. You know, a few years ago, I was rounding on a 3-week-old 26 weeks' gestation infant with severe IUGR and the IUGR had been contributed to maternal chronic hypertension for which the infant was delivered. The infant was on high-frequency ventilation at that time and a chest x-ray was suggestive of pneumonia. And then, I noticed that the direct bilirubin was increasing and the patient actually had persistent thrombocytopenia present from birth. At that time, we considered CMV as a differential and all other investigations confirmed CMV and, subsequently, the infant was treated for CMV.

The point is to consider congenital CMV on the differential especially with unexplained IUGR, persistent thrombocytopenia and elevated liver enzymes. So talking about the presentation, let's move on to the investigation. So clinically, you suspect CMV, how would you confirm the diagnosis of CMV?

Dr. Lee: So the gold standard to detect CMV is through viral culture. However, that has been replaced with CMV PCR of bodily fluids, such as urine, saliva or blood, because of several different reasons. The first is it only requires one sample and it is more sensitive and quicker to result. And it also provides a quantitative viral load.

Dr. Sharma: Yes, I agree. The CMV PCR has made it so much faster to make a diagnosis and has been very much welcomed.

Dr. Lee: Yep. So Dr. Sharma and our listeners, you may also be wondering about antibody testing with IgG and IgM that is available; however, that is to detect past infection, for reinfection or an acute infection. However, there is no clear role for CMV antibody testing of infants because maternal IgG antibodies can cross the placenta and, therefore, it is not diagnostic of a congenital CMV infection and IgM testing has limited predictive value. So other additional workup for suspected congenital CMV infection should include a CBC to screen for hematologic effects, such as neutropenia and thrombocytopenia, evaluating for elevated liver transaminases, obtaining CNS imaging, such as a head ultrasound or brain MRI, an eye exam to evaluate for chorioretinitis and, of course, a hearing screen.

Dr. Sharma: So Dr. Lee, what we just discussed is about the investigations in those patients that we clinically suspect to have CMV or those who are symptomatic. But how about infants who are asymptomatic or have asymptomatic CMV? How can we diagnose these patients? Because as you mentioned, hearing loss can be one of the sequelae of asymptomatic CMV. And we need to be able to pick these patients up so that they get their required treatment. So how about asymptomatic CMV? How do we diagnose it?

Dr. Lee: So, as we've already mentioned in the previous podcast, newborns are not routinely screened for CMV. However, the universal newborn hearing screen is the standard of care and is mandated in at least 45 states in the United States. According to the CDC in 2017, over 98% of newborns were screened for hearing loss and that accounts testing over 4 million newborns born. Many states have legislation requiring hospitals to provide parents of infants who fail the newborn hearing screen with information about congenital CMV and an opportunity to test for congenital CMV. Also, some hospitals have policies in place for reflexive CMV testing in newborns with a failed hearing screen before hospital district.

Dr. Sharma: So Dr. Lee, this is hot off the press. So I was aware that Minnesota was working towards trying to add CMV screening in the newborn screen. And actually, just last week on February 2nd this year, the governor of Minnesota actually approved the recommendation to add CMV to the state's newborn screen. So if that all goes through, then Minnesota will be the first and at least for now only state in the US that screens for CMV as part of the newborn screen. But interestingly, they have yet to decide and determine exactly what lab methods they will use to screen for CMV as part of their newborn screen. So, more to come.

Dr. Lee: That is very interesting, Dr. Sharma, and we will have to wait as more comes about of this.

Dr. Sharma: So we've now evaluated our patient. Can we talk about the management of neonates with CMV infection and let's first talk about asymptomatic CMV infection. What do we do about the asymptomatic patients?

Dr. Lee: So currently, there is no data suggesting benefit in treating asymptomatic or those with isolated sensory neural hearing loss and are otherwise asymptomatic. For neonates with symptomatic congenital CMV, the treatment is with oral valganciclovir or IV ganciclovir for those who are unable to take enteral medications. And for all of our listeners and learners, I wanted to stress the importance that recent studies report that symptomatic infants who received antivirals with either valganciclovir or ganciclovir for six months have improved hearing and higher language and receptive communication scores at two years of age, when compared to those infants who received no treatment, as well as those infants who are treated for six weeks.

Dr. Sharma: So Dr. Lee, just listening to you, one of the things that comes to mind is why doesn't acyclovir work on CMV infection when it is also a herpes virus? Do you know why?

Dr. Lee: Yes, Dr. Sharma. So it is very interesting because, although CMV is a herpes virus, acyclovir has no efficacy in CMV because unlike other herpes viruses, CMV does not replicate using thymidine kinase, which acyclovir requires. And because of that, the treatment for CMV is oral valganciclovir or IV ganciclovir.

Dr. Sharma: Dr. Lee, thanks for that interesting fact, which I did not think of. I guess we need to go back to pharmacology days. So moving on, both ganciclovir and valganciclovir have certain side effects that we have to be aware of. Can you talk about those?

Dr. Lee: Yes, Dr. Sharma, that is a very important question, especially since these neonates will need to be treated for six months. Neonates should be monitored for neutropenia, thrombocytopenia, hepatotoxicity and nephrotoxicity secondary to medication side effects.

Dr. Sharma: So apart from the treatment, which you have described very well, what other investigations we need to consider as part of management and followup of these patients?

Dr. Lee: So while not all infants with symptomatic disease at birth will have neurologic impairment, increasing data or correlating abnormal cerebral imaging with long-term neurodevelopmental sequelae therefore obtaining further imaging should be considered. And all affected neonates should receive audiologic hearing test to evaluate for hearing loss.

Dr. Sharma: So Dr. Lee, even if there is no hearing loss initially, infants with CMV need followup hearing test. Can you talk more about what followup is needed? Because I think that is very important.

Dr. Lee: Absolutely, Dr. Sharma. Because these infants are at high risk for hearing impairment, they should continue to receive hearing screenings at every three to six month intervals until four years of age and annually until at least 18 years of age and referral for hearing aid selection and fitting should be done as early as possible within one month after the diagnosis of hearing loss and in addition to referral to early intervention and neurodevelopmental support, which are critical in optimizing the outcomes of these higher risk infants.

Dr. Sharma: So with the management and followup completed, how about prevention? Are there ways to prevent congenital CMV infection?

Dr. Lee: That is a great question. We've all heard this often, especially during the current COVID pandemic, but hand hygiene is the best way to decrease CMV transmission, especially for pregnant women and women of childbearing age who care for young children, such as in daycares or nurseries. Additionally, it was recently reported that maternal CMV immunoglobulin is not effective for preventing congenital disease. And there's also currently no CMV vaccine available for use in humans, which therefore hand hygiene still remains the best way to prevent CMV infection. I also wanted to add that pasteurization of donor breast milk as well as freezing fresh human breast milk can decrease the viral load of CMV and thus decrease the likelihood of CMV transmission through breast milk.

Dr. Sharma: Dr. Lee, that's such good information about how infants who are infected with CMV and the use of breast milk. My understanding is this is no longer controversial.

Dr. Lee: You are absolutely correct. For infants who are already infected with CMV, the benefits of human milk from their mothers likely outweighs any risk of additional CMV exposure. Therefore, common practice is to continue using thawed breast milk.

Dr. Sharma: Dr. Lee, you have discussed some very important aspects of CMV infection, specifically on the evaluation, management and prevention of congenital CMV infection. Can you please summarize the final key points?

Dr. Lee: For our listeners, some final key points are postnatally acquired CMV infection after three weeks of age is usually clinically benign or self-limited and does not have the same constellation of symptoms or risk for hearing loss as compared to congenital CMV infection. Also, treatment of symptomatic neonates is with ganciclovir or valganciclovir for six months, as it has been shown to improve audiologic and neurodevelopmental outcomes at two years of age. All affected neonates should receive audiologic hearing tests to evaluate for hearing loss at increased screening intervals, because these infants are at higher risk for hearing impairment. And lastly, if our listeners are interested, there's an international consensus recommendation published for congenital CMV diagnosis and management that they can check out online if interested.

Dr. Sharma: So Dr. Lee, before we end, do you have questions for us?

Dr. Lee: Yes, Dr. Sharma, we have two questions to review CMV. So the first question is: You are caring for a two-week-old small for gestational age preterm infant with persistent thrombocytopenia, hepatomegaly and calcifications found on the screening and ultrasound. You diagnose congenital CMV and confirm it with urine PCR testing. The treatment for this infant is, A, no treatment is necessary, it will self-resolve; B, acyclovir for six weeks; C, valganciclovir for six weeks; or D, valganciclovir for six months.

Dr. Sharma: Okay, Dr. Lee. So this patient has symptomatic congenital CMV infection. So A is incorrect. B is definitely incorrect because we talked about why acyclovir doesn't work for CMV although CMV is also a herpes virus. And then we talked about valganciclovir for six weeks is less effective than the six-month course. So the answer is D.

Dr. Lee: You are correct, Dr. Sharma. Valganciclovir for six months is the treatment for symptomatic congenital CMV. And so for question two, the same two-week old preterm infant with congenital CMV is now ready to begin enteral feeds. The mother is worried her breast milk is infected with CMV and asks if she can still use her breast milk, which is the correct answer? A, no, the infant will be reinfected; therefore, the team will use preterm formula only; B, the mother may take antiviral medications for six weeks and then may provide her fresh breast milk to be used; C, yes, however, freezing her breast milk will decrease the viral load; therefore, it is recommended to use frozen then thawed milk rather than fresh breast milk; or D, yes. However, only after the infant completes the antiviral course as to not get reinfected.

Dr. Sharma: Okay. Dr. Lee, we did discuss this in the podcast earlier. And the answer is C, that mom can provide her breast milk after freezing, which will decrease the viral load. So answer is C.

Dr. Lee: Yes. Dr. Sharma, you are correct. So the benefits of using maternal human milk outweighs any risk or additional CMV exposure. So the common practice is to continue using thawed milk rather than fresh breast milk.

Dr. Sharma: Thank you so much, Dr. Lee, for giving your time to discuss perinatal and neonatal CMV infection. Thank you for listening, everyone. Hopefully, we provided you with a lot of information in the last two episodes on congenital CMV. This is Neonatology Review: Isolette to Crib. And I'm your host, Dr. Jyoti Sharma signing off. Until next time, happy listening.